Assessing anatomical distribution of atopic dermatitis identifies a cluster of patients with late onset and low risk of asthma and allergy: An observational study

Abstract Background and Aims A better understanding of distinct subgroups in atopic dermatitis (AD) is warranted. The aim was to identify and determine characteristics of clusters based on anatomical location of AD. Methods In this 8‐week, observational, decentralized study, patients with AD completed a baseline questionnaire about anatomical location and severity of AD, and a principal component analysis (PCA) was applied to identify clusters. The Patient‐Oriented Eczema Measure (POEM) was completed weekly and photographs of affected body areas were captured by the participants' own smartphones. From the weekly photographs, the AD severity was evaluated using the intensity part of the SCORing Atopic Dermatitis. Results Fifty‐five participants were recruited, of which 53 completed the baseline questionnaire with a mean POEM of 14.5 (SD: 5.6). The PCA analysis revealed three clusters, with AD predominantly on the shins, knees, and genitals (Cluster 1), with involvement of the upper body (Cluster 2), and with AD on the hands and feet (Cluster 3). Cluster 1 had a lower mean POEM score (11.12, SD: 5.3) compared with Clusters 2 (12.64, SD: 4.5) and 3 (15.98, SD: 4.7), respectively (p = 0.007). Further, Cluster 1 had the highest age of AD onset (mean 9.5 vs. 2.5 and 4.7 years, p = 0.02) and the lowest proportion of asthma/allergy (47% vs. 82% and 90%, p = 0.01). Conclusion Three clusters of patients with AD based on affected body areas were identified. The cluster with involvement of legs and genitals was characterized by the oldest age of AD onset and the lowest prevalence of asthma/allergy.


| INTRODUCTION
Atopic dermatitis (AD) is a chronic, severely pruritic, skin disease that prominently reduces the quality of life of affected patients. 1 AD is characterized by skin inflammation along with skin barrier dysfunction 2 and affects different body areas depending on the age of the patient. The face and neck are commonly affected in infants and small children; flexural involvement is common in later childhood and adolescence, whereas in adults, the face, hands, and feet are more often affected. 3 Common features seen in patients with AD are dry skin, early disease onset (<2 years), and a personal history and/or family history of atopic disease (e.g., AD, asthma, allergic rhinitis) or specific IgE reactivity. 4 Early-onset AD is the most common type; around 50% of all patients with AD develop symptoms within the first year of life and around 95% experience an onset below 5 years of age. 5 Predictors of AD activity beyond childhood and into adulthood include concurrent asthma, allergic rhinitis, young age of onset, low socioeconomic status, and non-White ethnicity. 6,7 AD is a heterogeneous disease and can be categorized in many phenotypes based on age of onset, disease severity and clinical or morphological features (eg. nummular eczema, atopic prurigo, lichen planus-like, pityriasis alba). 8 AD can also be categorized in extrinsic and intrinsic subtypes based on IgE levels and intrinsic AD is defined by female predominance and lack of association with respiratory atopy. 9 To facilitate the development of successful prevention and treatment strategies, it is important to define the different phenotypes or subgroups of AD, and to evaluate the characteristics of these subgroups and associations with atopic diseases.
The aim of this study was to identify clusters of body areas affected by AD in adults, determine characteristics of these clusters based on age of onset and other atopic diseases, and to explore patterns of subjective and clinical changes, based on photographic assessments of AD lesions, in disease activity over time.

| METHODS
The present study is a first-time analysis of AD data from a previously published 8-week, noninterventional, observational, fully remote decentralized feasibility study including patients with AD, designed to investigate whether a siteless trial could recruit nationwide, achieve high adherence, and prevent dropouts. 10 Patients with AD were recruited online through advertisements on social media (recruitment data are published elsewhere 10 ), and were included if they were 18 years or older, fulfilled the UK Diagnostic Criteria for Atopic Dermatitis, 11 and had at least one visible AD lesion at the time of recruitment. The AD lesion was confirmed by board certified dermatologists on a photograph taken by the patient as the study was decentralized without visit to a clinical study site.
At baseline, the participants completed a questionnaire about body areas (scalp, face, neck, shoulders, arms, hands, chest, back, stomach, genitals, thighs, knees, shins, and feet) affected by AD and self-reported AD severity at the affected body areas (none, mild-to-moderate, or severe). Throughout the study period, all study related tasks were performed from patients' own homes, as previously described. 10 In brief, each week all participants received an email prompting them to capture a photograph of the affected skin and with a link to an online questionnaire (Google Forms). The Patient-Oriented Eczema Measure (POEM), 12 is a validated, reliable, and simple tool for measuring AD severity. The POEM scores can range from 0 to 28 and have shown longitudinal sensitivity to changes in activity of AD experienced by the patient. 12 POEM items assess the frequency of itching, sleep disturbance, dryness, flaking, cracking, bleeding, and weeping/oozing because of AD during the past week.
POEM was completed weekly along with photographs of affected body areas captured by the participants' own smartphones.
From POEM changes in dryness, flaking, cracking, bleeding, and weeping/oozing skin was extracted. SCORing Atopic Dermatitis (SCORAD) is a clinical tool to assess the severity of AD as an objective measure. 13 From the photographs, the AD severity was evaluated using the intensity part of the SCORAD (iSCORAD). The iSCORAD is based on the ratings of the following six items: erythema, edema/papulation, excoriations, lichenification, oozing/crusts, and dryness, graded on a scale of 0-3.

| ETHICS
Danish Regional Committee on Health Research Ethics was consulted before execution and the study did not require ethical approval (protocol number:16025688). The study was carried out according to Danish law.

| Statistics
Baseline variables were reported as means and SDs for continuous The Kruskal-Wallis test by ranks and Pearson's χ 2 test along with Fisher's exact test was used to calculate two-sided p values. A p < 0.05 was considered statistically significant.
All analyses were performed using the statistical software R.

| RESULTS
Fifty-five patients were recruited of which 53 completed the baseline questionnaire with a mean POEM of 14.5 (SD: 5.6) (range: 6-28). The body areas most often affected at baseline were the arms, hands, face, and neck, whereas the least often affected areas (reported as being without AD) were the stomach, genitals, knees, shins, and feet.
The body areas most often reported as severe were the face, neck, arms and hands, whereas the body areas that were more commonly reported as mild-to-moderate were the scalp, face, neck, arms, hands, and thighs ( Figure 1).
The PCA analysis revealed three clusters corresponding to patients, respectively, as follows: AD predominantly on the shins, knees, and genitals (Cluster 1); on the upper body, especially the neck and face, shoulders, and arms (Cluster 2); and on the hands and feet  Table 1). The reduction in POEM scores in Cluster 1 was driven by improvement of itch and sleep, which were the only elements with a decline in slope; however, these changes within Cluster 1 over time were not statistically significant and neither was the difference in slope between the clusters (Table 1). No clear change in self-assessed AD activity in terms of changes in skin symptoms (as indicated with the slope estimates for bleeding, weeping/oozing, cracked, flaking, or dry skin) ( Table 1) Figure 4C). Further, no F I G U R E 1 Self-reported body areas with atopic dermatitis at baseline (A) and self-reported severity in these areas (B). significant differences were seen in the change (slope) of iSCORAD ( Figure 4D). Cluster 1 had a significant lower proportion of participants with early (<2 years) disease onset (20%) compared with Clusters 2 (65%) and 3 (57%) (p = 0.02). Further, the percentage of participants with other atopic diseases (asthma or allergy) was also lowest in Cluster 1 (47%) compared with Clusters 2 (82%) and 3 (90%) (p = 0.01). A tendency was observed toward lower use of moisturizers, systemic treatment, and phototherapy for AD at baseline in Cluster 1 ( Table 2).

| DISCUSSION
In this decentralized study with remotely collected patient reported data, three clusters of patients with AD based on anatomical distribution of eczema were identified: the first cluster was characterized by AD on legs and genitals, the second was characterized by involvement of the upper body, whereas the third was     before age 2 years. 14 The median age of onset was 5 years in Cluster Lastly, the data on other atopic diseases, age of onset, and treatment was self-reported and could potentially be affected by recall bias.
Moreover, there may also be bias associated with self-reported data.
In conclusion, three clusters of patients with AD based on affected body areas were identified. One cluster with AD on legs and genitals, one with involvement of the upper body, and one with AD on the hands and feet.

ACKNOWLEDGMENTS
The study was funded by Studies&Me. The funding source was involved in caring out the analysis. The funding source did not have any role in the decision to submit the report for publication.

CONFLICT OF INTEREST STATEMENT
Zarqa Ali and Simon F. Thomsen

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.

TRANSPARENCY STATEMENT
The lead author Zarqa Ali affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.